NR4A orphan nuclear receptors modulate insulin action and the glucose transport system: potential role in insulin resistance.

After observing that expression of two NR4A orphan nuclear receptors, NR4A3 and NR4A1, was altered by insulin in cDNA microarray analyses of human skeletal muscle, we studied whether these receptors could modulate insulin sensitivity. We found that both NR4A3 and NR4A1 were induced by insulin and by thiazolidinedione drugs (pioglitazone and troglitazone) in 3T3-L1 adipocytes. Furthermore, gene expression of NR4A3 and NR4A1 was reduced in skeletal muscles and adipose tissues from multiple rodent models of insulin resistance.

Proinflammatory cytokine production and insulin sensitivity regulated by overexpression of resistin in 3T3-L1 adipocytes.

Resistin is secreted from adipocytes, and high circulating levels have been associated with obesity and insulin resistance. To investigate whether resistin could exert autocrine effects in adipocytes, we expressed resistin gene in 3T3-L1 fibroblasts using a lentiviral vector, and selected several stably-transduced cell lines under blasticidin selection. We observed that 3T3-L1 adipocytes expressing resistin have a decreased gene expression for related transcriptional factors (CCAAT/enhancer binding protein alpha(C/EBPalpha), peroxisome proliferator-activated receptor gamma (PPARgamma), and adipocyte lipid binding protein (ALBP/aP2) which is one of target genes for the PPARgamma during adipocyte differentiation,.

Lipid metabolism mediated by adipocyte lipid binding protein (ALBP/aP2) gene expression in human THP-1 macrophages.

The critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial wall of arteries, and their transformation from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). We previously reported that adipocyte lipid binding protein (ALBP/aP2) is a gene that is highly up-regulated in foam cells in response to oxLDL.